While local therapies are relatively effective in combating prostate cancer (CaP), treatment for disseminated disease is the withdrawal of androgens, which is only palliative. However, CaP eventually continues to grow in an androgen-independent or castration-resistant state. Great effort has focused on understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer (CRPC). Androgen receptor (AR) appears to play a central role in the development and progression of CRPC. Although circulating androgens remain very low or undetectable in the castrate environment, AR is expressed at high levels and AR-regulated genes are expressed. AR activation in CRPC may occur by a variety of mechanisms that alter the sensitivity or specificity of AR. In addition, CRPC has intraprostatic androgen levels sufficient to activate AR. We and others have demonstrated that interleukin-6 (IL-6) activates AR and increases cell survival after castration. In addition, we demonstrated that coactivator, TIF2, plays critical role in IL-6-mediated antiandrogen resistance. Most recently, we demonstrated that IL-6 increases the expression of genes encoding many steroidogenic enzymes including HSD3B2 and AKR1C1-3 involved in androgen biosynthesis, which suggest that IL-6 may increase the levels of intraprostatic androgens. This finding is clinically significant, since recent studies showed that HSD3B2 and AKR1C1-3 expression is significantly elevated in CRPC. Furthermore, IL-6 induces neuroendocrine cell differentiation, which correlates with tumor progression, poor prognosis, and CRPC. The central hypothesis of this application is that IL-6 promotes castration-resistant prostate cancer (CRPC) by activating AR signaling through alteration of intraprostatic androgen synthesis and coregulator expression during androgen deprivation therapy. In this proposal, we will focus our research on defining the roles of IL-6 in intracrine or intraprostatic androgen biosynthesis and in affecting coregulator expression. There are three aims of this proposal; the first aim is to understand the role of IL-6 in androgen responsiveness and prostate cancer progression. The second aim tests that IL-6 induces intracellular androgen biosynthesis and their potential role in mediating CRPC growth. The last aim is designed to study the effects of coregulators in mediating IL-6 induced AR activation. Completion of these studies will provide the vital role of IL-6 in castration resistant prostate cancer, and will likely present an excellent diagnostic and/or prognostic indicator and allow physicians to better manage individual treatment regimes. PUBLIC HEALTH RELEVANCE: Patients with prostate cancer initially respond to androgen deprivation therapy. However, virtually all patients will relapse due to acquisition of the growth of castration resistant tumor cells. Understanding the molecular mechanisms leading to castration resistance is the key to develop successful therapies to combat this lethal response. The present proposal directly deals with the mechanisms of this evolution and has identified a critical factor involved in this process. The central hypothesis of this application is that interleukin-6 promotes castration-resistant prostate cancer by activating androgen receptor signaling through alteration of intraprostatic androgen synthesis and coregulator expression during androgen deprivation therapy. Our important mechanistic and pre-clinical studies will serve as the foundation for development of a mechanism based castration-adjunctive therapy, which may lead to a more effective intervention than castration alone.